1. Field of the Invention
Drug and gene delivery to solid tissues is of significant medical and scientific interest. Most simply, drugs and genes can be injected into muscle, organs, and other solid tissues using a needle under pressure, typically provided by a syringe. While many small molecule drugs are adequately taken up by such straight-forward injection methods, the delivery and uptake of large molecules (such as proteins) and genes (and other nucleic acids) is often more problematic. In particular, the successful delivery of functional genes to solid tissues such that the genes are expressed can often be quite difficult.
Various methods for enhancing the delivery of genes and other large molecules have been proposed. Of particular interest to the present invention, the application of an alternating electric field across the target tissue, referred to as electroporation, has been found to be of significant benefit in enhancing expression, particularly in research settings. Such application of an alternating electric field can open pores in the cellular membranes of the target tissue, allowing functional genes and other large molecules to be delivered into the cell. The application of electroporation in experimental gene therapies has been found to substantially increase successful cell transformation.
The development of successful clinical electroporation devices has been very slow. One drawback has been the need to apply relatively high voltages to achieve the needed voltage gradients at the target cells. At present, electroporation is usually accomplished by attaching a single needle or a needle array to one pole of the electroporation power supply and attaching the other pole to another needle, needle array or surface electrode. Typically, the distance between the electrode pairs is very large, often several centimeters or larger, requiring high voltages, on the order of 1,000 volts or above, to achieve the necessary voltage gradients at the target tissue. Such high voltages can cause undesirable tissue damage. A second drawback has been the use of large arrays comprising many needles. Many patients recoil when feeling such apparatus.
For these reasons, it would be desirable to provide improved methods and apparatus for the electrically-enhanced delivery of genes and other large molecules to cells within solid target tissues. In particular, it would be desirable to provide methods and apparatus which could operate at lower voltages and/or with fewer penetrating structures to reduce the risk of tissue injury and damage. It would be further desirable to provide such electrically enhanced methods and apparatus which could be utilized in intravascular, minimally invasive, and other body locations which require miniaturized access tools. At least some of these objectives will be met by the inventions described hereinafter.
2. Description of the Background Art
Microneedles and electroporation apparatus are described in U.S. Pat. Nos. 6,334,856; 6,331,266; 6,312,612; 6,241,701; 6,233,482; 6,181,964, 6,090,790; 6,014,584; 5,928,207; 5,869,326; 5,855,801; 5,823,993; 5,702,359; 5,697,901; 5,591,139; 5,389,069; and 5,273,525. Electroporation methods are described in Varenne and Sinnaeve (2000) Current Int. Cardiol. Reports 2:309. The fabrication of silicon and paylene microneedles is described in Stupar and Pisano (2001) Transducers '01, 11th Int'l Conference on Solid-State Sensors and Actuators, Munich, Germany, Jun. 10–14, 2001. The full disclosures of each of these prior patents and publications are incorporated herein by reference.